This invention relates to copolymers of p-dioxanone and 2,5-morpholinediones and surgical devices formed therefrom, having accelerated absorption characteristics.
Absorbable surgical devices, including suture materials have traditionally been natural collagenous materials obtained from sheep or beef intestine, commonly known as catgut. More recently, it has been proposed to manufacture synthetic absorbable sutures from polyesters of hydroxycarboxylic acids, notably polylactide, polyglycolide, and copolymers of lactide and glycolide. Such synthetic absorbable sutures are described in U.S. Pat. Nos. 3,636,956, 3,297,033 and elsewhere in the literature.
Among the requirements of an ideal absorbable suture are that it should have good handling properties, should approximate and hold tissue for proper healing with minimal tearing and tissue damage, should have adequate straight tensile and knot strength, should be controllably uniform in properties including dimensional stability within the body, should be sterilizable, should be absorbable by living tissue, preferably at a constant rate regardless of the place in the body or the condition of the patient, without causing such unfavorable tissue reactions as walling off, granuloma formation, excessive edema, etc., and finally should be capable of being properly and easily tied into surgical knots.
While multifilament sutures manufactured from polymers of lactide and glycolide fulfill the above requirements to a large degree, monofilament sutures of these materials are considerably less flexible than catgut and these synthetic sutures are accordingly generally limited to a multifilament, braided construction.
In U.S. Pat. No. 4,052,988 there is described polymers of p-dioxanone and 1,4-dioxepan-2-one which can be melt extruded into pliable, monofilament fibers which are slowly absorbed in animal tissue without significant adverse tissue reaction and which have good tensile and knot strength and good in vivo strength retention. However, the absorption characteristics of said polymers are not as fast as would be desirable for certain purposes.
Although U.S. Pat. Nos. 3,063,967 and 3,063,968 describe the polymerization of p-dioxanone and the preparation of films and fibers therefrom, the low tensile strength of fibers prepared in accordance with the teachings of the latter two references, however, make these fibers generally unsuitable for use as surgical sutures. Moreover, there was no appreciation in said latter two references of the absorbability of such fibers which were reported to be resistant to the effects of saline and distilled water.
Other references dealing with the polymerization of p-dioxanone include, but are not limited to, U.S. Pat. Nos. 3,190,858, 3,391,126 and 3,645,941 which disclose various catalysts for the polymerization of lactones such as p-dioxanone, and U.S. Pat. No. 3,020,289 which describes the polymerization of p-dioxanone in the presence of sulfuric acid. None of these references suggest polymers of p-dioxanone for use in the preparation of synthetic absorbable sutures. M. Goodman and his coworkers (see the eight references listed below) prepared several polydepsipeptides (copolymers with repeat units originating from separate derivatives of .alpha.-amino and .alpha.-hydroxy acids) by the copolymerization of the appropriate cyclic anhydrides of these monomers. Available data do not suggest that these investigators were able to prepare alternating type polydepsipeptides by this route or the direct homopolymerization of the cyclic codimers morpholinediones to form truly regular polydepsipeptides with alternating peptide and ester repeat units. These were never alluded to in any of Goodman's reports. This may be attributed to their inability to prepare morpholine-2,5-diones which are polymerizable to alternating polydepsipeptides. The polydepsipeptides reported by Goodman et al. in U.S. Pat. No. 3,773,737 were described as hydrolytically more stable and hence are less absorbable than polylactides, polyglycolide or polydioxanone.
1. Nissen, D., Gilon, C. and Goodman, M, 1975, Macromol. Chem., Suppl. 1, 23. PA0 2. Mathias, L., J, Fuller, W. D., Nissen, D. and Goodman, M., 1978, Macromolecules 11, 534. PA0 3. Ingwall, R. T. and Goodman, M., 1974, Macromolecules 7, 598. PA0 4. Ingwall, R. T., Gilon, C. and Goodman, M., 1976, Macromolecules 9, 802. PA0 5. Ingwall, R. T., 1978, Macromolecules 11, 540. PA0 6. Goodman, M., Gilon, C., Palumbo, M. and Ingwall, R. T., 1974, Isr. J. Chem. 12, 67. PA0 7. Goodman, M., Gilon, C., and Kirshenbaum, G. S. and Knobler, Y., 1972, Isr. J. Chem. 10,867. PA0 8. Goodman, M., and Kirshenbaum, G. S., (1973) U.S. Pat. No. 3,773,737.
We have discovered that the rate of absorption of polydioxanone such as that disclosed in U.S. Pat. No. 4,052,988, may be enhanced by incorporating 1-15 mole percent of 2,5-morpholinedione or its alkyl substituted derivatives in the chain as a comonomer without adversely affecting the breaking strength retention profiles of the unmodified homopolymer. Furthermore, contrary to what would be expected from the general teachings of Goodman et al. in U.S. Pat. No. 3,773,737, the present copolymer displays a much lower hydrolytic stability as compared to the polydioxanone of U.S. Pat. No. 4,052,988.